Highly regioselective and diastereoselective synthesis of novel pyrazinoindolones via a base-mediated Ugi-N-alkylation sequence

An efficient base-mediated/metal-free approach has been developed for the synthesis of 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide derivatives via intramolecular indole N–H alkylation of novel bis-amide Ugi-adducts. In this protocol the Ugi reaction of (E)-cinnamaldehyde derivatives, 2-chloroaniline, indole-2-carboxylic acid and different isocyanides was designed for the preparation of bis-amides. The main highlight of this study is the practical and highly regioselective preparation of new polycyclic functionalized pyrazino derivatives. This system is facilitated by Na2CO3 mediation in DMSO and 100 °C conditions.


Introduction
Nitrogen-containing heterocycles are really important structural motifs with large applications in medicinal, 1,2 pharmaceutical, 3 and synthetic organic chemistry. 4 Among them the indole ring is present in many important natural products 5,6 and is a basic skeleton of a number of drugs. 2,7 Additionally, fused indole rings have the affinity to bind to receptors. 8,9 Hence, the preparation of fused and derived indoles has attracted much attention from organic chemists for many years. [10][11][12][13] Indole and pyrrole fused-piperazine and piperazinone derivatives are signicant heterocycle compounds used as pharmacophores due to their potential medicinal activities. 14,15 Investigations on these tricyclic nucleuses started in 1994, when they were studied from two points of view: synthetic and potency in medical science. [16][17][18] In this class, pyrazino [1,2-a] indolones are very important tricyclic backbones, such as indole joined into a piperazinone ring. These analogues are under great consideration due to their therapeutic uses. 19 Pyrazino[1,2-a]indol-1-one derivatives are impressive pharmacophores in the treatment of various diseases. 19 Several of them have potent inhibitory 19 and anti-cancer activities (Fig. 1A, C and D), 10,19,20 and some of them have anti-infection, 21 anti-allergenic 22 and anti-viral properties (Fig. 1B). 23 Compounds containing pyrazinoindolone frames have been reported as potent mitogen-activated protein kinase-2 (MK 2 ) inhibitors. 24,25 Despite the importance of indole-fused structures, a few effective procedures have been reported for their synthesis. A series of substituted-3,4-dihydropyrazinoindol-1(2H)-one was synthesized by Toche et al. 26 from the cyclization reaction of ethyl 1-(2-bromoethyl)-1H-indole-2-carboxylate and primary amines. In another work, Youssif et al. 10 prepared open-chain indole-2-carboxamides and then performed consequential oxidation and cyclodehydration using PTSA which resulted in the production of benzyl pyrazino[1,2-a]indol-1(2H)-ones. In 2017, Kim et al. 20 reported on the preparation of biologically active 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3carboxamide analogs in three steps.
Because of the application of pyrazinoindolones in drug discovery, designing a novel and efficient pathway for their synthesis is tempting enough for synthetic chemists. Currently, Ugi four-component reaction has provided good conditions to synthesize diverse N-heterocyclic structures. [27][28][29] This name reaction in combination with other reactions is converted to a remarkable tool to prepare new fused scaffolds. 30 Since the beginning of the 21st century, various examples have been reported using this combinatory protocolas post-Ugi process. These strategies include Ugi/Heck, 31,32 Ugi/Diels-Alder, 33 Ugi/ Buchwald-Hartwig, 34 Ugi/Knoevenagel condensation, 35,36 etc.

Results and discussion
In continuation of our efforts to indole chemistry and multicomponent reactions, [39][40][41] we focused on the preparation of tetrahydro-pyrazino[1,2-a]indol-1-ones using the posttransformation of Ugi adducts, under metal-free conditions.
Despite the positive effect of the presence of transition metals on the yield of many organic reactions 42,43 these reactions suffer from some limitations such as the high costs of metals and their removal from the reaction medium. 29 Considering these disadvantages and the low efficiency of the procedure in the absence of transition metals, we have reported an efficient base-mediated strategy for the preparation of new 1oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamides.
In the rst step, the Ugi condensation of aromatic aldehydes like cinnamaldehyde derivatives, anilines, 1H-indole-2carboxylic acid and diverse isocyanides led to the formation of bis-amides in methanol ( Table 1).
The prepared bis-amide products are unique due to the presence of several potent nucleophilic sites (Scheme 1a-e) and the leaving groups (Scheme 1f-h) that are located on Ugi products, so they are highly predisposed to intramolecular condensation. Because of the presence of these active sites, we tried to do a post sequential reaction of these Ugi adducts. Initially, the reaction was studied with 5a (derived from cinnamaldehyde, 2-chloroaniline, 1H-indole-2-carboxylic acid and cyclohexyl isocyanide) as the model in the presence of Pd(OAc) 2 / Ph 3 P, K 2 CO 3 under CH 3 CN reux conditions, but we did not obtain any products (Table 2, entry 1). Changing the solvent to DMSO, provided 6a with 80% yield (Table 2, entry 2). Aer the identication of the product, it was determined that only indole N-H alkylated one was formed among the possible products (based on their nucleophilic and electrophilic positions) (Scheme 1).
The N-alkylation and arylation of indole are a noteworthy tool for carbon-nitrogen bond formation, because of the vast application of N-heterocycles in natural products and bioactive drugs. [44][45][46] To date, there have been several attempts at designing mild strategies towards N-alkylated indoles, under metal-catalyzed or catalyst-free conditions. [46][47][48] To continuation the optimization process, different metals/ ligands like PdCl 2 /Ph 3 P and CuI/L-proline were studied, but no preference was observed compared to Pd(OAc) 2 /Ph 3 P ( Table 2, entries 4 and 5).
Surprisingly, performing the reaction in the absence of metal/ligand did not show a signicant decrease in the product yield (Table 2, entry 6, 78% yield for 6a). In the next step, different temperatures of 50°C, to 120°C were investigated. According to the results, there was no remarkable yield difference between the reactions at 100 and 120°C, but decreasing the temperature to 50°C or to RT lowered the yields of the reactions ( Table 2, entries 6-9). Then, the inuence of diverse solvents was examined and the presence of DMSO showed the best effectiveness (Table 2, entries 7 and 10-12). Some alkaline metal bases were examined in order to comprehend the effect of the base nature. The metal bases mentioned in Table 2 (Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , KOH, KOt-Bu) showed very good positive results (entries 13-16), but a negative effect on yield was observed in the presence of triethylamine and diazabicyclo [2,2,2] octane (DABCO) as the organic bases, negative effect on the yield was observed ( Table 2, entries 17 and 18). Additionally, performing the reaction in the absence of base led to the desired product 6a with the yield of 32% (Table 2, entry 19).
The scope of this Ugi-N-alkylation sequence process was explored under optimized reaction conditions (2 equiv. of Na 2 CO 3 as base, DMSO as solvent, 100°C temperature, 4 h) (Table 2, entry 7). The results are summarized in Table 3.
Ugi products (Table 3) containing electron-withdrawing and electron-donating substituents, reacted under optimum conditions to produce the desired product with moderate to excellent yield. Generally, the best results were obtained using electrondonating groups on cinnamaldehyde part (6b), and less bulky groups on isocyanide part (6d). Ugi products with bulky isocyanide like isopropyl and t-butyl showed less reaction efficiency (6e, 6f). Product 6j was also separated with excellent yield, but because of its low solubility in DMSO it could not be identied.
In order to investigate the possibility of the reaction in the absence of chlorine substitution on the aniline ring, we applied p-toluidine as amine instead of 2-chloroaniline in the Ugi reaction and product 5p was obtained. This substrate, was treated with Na 2 CO 3 under optimized reaction conditions and generated post-Ugi product 6p with good efficiency.
Due to the presence of two chiral centers, two diastereomeric isomers were formed in the corresponding products, except for the compounds 6m and 6p, in which only one diastereomer was obtained. It is worth mentioning that indole N-H alkylation was successfully performed without protection of the second N-H function group. This issue is evident from the elimination of the indole N-H peak in the 1 H NMR spectrum.  The structure of compound 6b was determined by X-ray crystallographic analysis to get a better view about the composition structure of these products. The X-ray diffraction data analysis revealed that 6b got crystallized in monoclinic space group P2/n. The asymmetric unit is composed of two 6b molecules (A and B) but, one of them (A) is partially disordered and thus only one molecule (B) is presented in Fig. 2. In the crystal structure, the 1H-indole-2-carboxylic, 2-chloroaniline and cinnamaldehyde derivative (4-methoxybenzene) rings are at. A and B, respectively) calculated using program PLATON 50 for six-membered N-cyclohexylamide ring indicate its chair conformation. In the crystal structure, the molecules of 6b are linked into chains running along the b-axis by N3-H3/O1 i hydrogen bond [H/A = 2.01 Å, D/A = 2.867(5) Å, D-H/A = 164°, (i) x, y + 1, z] involving the atom H3 of the N-cyclohexylamide NH group as a donor and the carbonyl O1 atom of 1H-indole-2-carboxylic group as an acceptor (Fig. 3).
The analysis using PLATON 50     A plausible mechanism for this diastereoselective cyclization is presented in Scheme 2 based on the experimental results. First, carbanionic intermediate (1), is formed by the addition of base to Ugi substrate. The destabilization of carbanion (1) followed by neutralization led to intermediate (3). This intermediate can undergo intramolecular nucleophilic attack by the nitrogen atom of the indole moiety to generate the nal product via a 6-endo-trig cyclization.

Conclusion
In summary, we have reported a new sequential Ugi reaction/ NH-alkylation for the synthesis of novel tricyclic oxo-tetrahydropyrazino[1,2-a]indole-3-carboxamide derivatives. Various enals, anilines and isocyanides were subjected to this protocol and the products were obtained with high selectivity. Simple procedure, high yield of all products, chemo-and diastereoselectivity and metal-free condition are the main advantages of this method that can make it a practical synthetic route for the preparation of pyrazinoindolone derivatives.

Conflicts of interest
There are no conicts to declare.  Scheme 2 A plausible mechanism for the cyclization step of Ugi adducts.